This renewal program project grant seeks continued support for an integrated program of research aimed at understanding the cellular and molecular mechanisms involved in nerve fiber degeneration and regeneration in models of human neuropathy and in human neuropathy itself. A major focus is the study of diabetic neuropathy. The primary objective of Project 36 is: 1) to determine the staged prevalence of the major types of diabetic neuropathy in Rochester, MN; 2) to develop and validate meaningful measures of neuropathy and approaches to stage severity; and 3) to longitudinally assess occurrence of neuropathy over time, to ascertain changes in neuropathy over time and the risk factor with changes in neuropathy with time. Healthy subjects, randomly selected from the same population, are evaluated for the occurrence of neuropathy (to estimate frequency of neuropathy in controls). These subjects are re-evaluated 4 years later to determine change of neuropathic evaluation results with age. In Project 37 experimental and human nerve tissue is evaluated to: compare clinical to neuropathologic criteria for neuropathy, to assess the influence of metabolic derangements, and to assess for specific neuropathologic explanations for neuropathy. This human and experimental tissue is also studied to assess the hypothesis that microvessel complications are implicated in diabetic neuropathy. In Project 31 a repertoire of physiologic and biochemical techniques are used to assess for nerve ischemia in models of experimental diabetes. The studies will be extended to the cell body, and, based on insights gained from recent studies, will undertake 3 studies with treatment implications for human diabetic neuropathy. In Project 38, Poduslo and coworkers systematically explore the effect of glycation of sugars on their transfer characteristics across perineurial and endoneurial barriers. Does the increase transfer lead to accumulation of these glycated proteins and is it deleterious? Also assessed is whether glycation of protein might be exploited as a method of transferring needed metabolites or medication into nerve. In Project 39, Windebank studies experimental models of neuropathy (especially cisplatinum) as a realistic model of nerve fiber degeneration and regeneration and the influence of growth factors in development, regeneration, and prevention of nerve injury.